This invention pertains to the fields of immunodiagnostics and immunotherapeutics. In particular, this invention pertains to the discovery of novel human antibodies that specifically bind to c-erbB-2, and to chimeric molecules containing these antibodies.
Conventional cancer chemotherapeutic agents cannot distinguish between normal cells and tumor cells and hence damage and kill normal proliferating tissues. One approach to reduce this toxic side effect is to specifically target the chemotherapeutic agent to the tumor. This is the rationale behind the development of immunotoxins, chimeric molecules composed of an antibody either chemically conjugated or fused to a toxin that binds specifically to antigens on the surface of a tumor cell thereby killing or inhibiting the growth of the cell (Frankel et al. Ann. Rev. Med., 37: 127 (1986)). The majority of immunotoxins prepared to date, have been made using murine monoclonal antibodies (Mabs) that exhibit specificity for tumor cells. Immunotoxins made from Mabs demonstrate relatively selective killing of tumor cells in vitro and tumor regression in animal models (id.).
Despite these promising results, the use of immunotoxins in humans has been limited by toxicity, immunogenicity and a failure to identify highly specific tumor antigens (Byers et al. Cancer Res., 49: 6153). Nonspecific toxicity results from the failure of the monoclonal antibody to bind specifically and with high affinity to tumor cells. As a result, nonspecific cell killing occurs. In addition, the foreign immunotoxin molecule elicits a strong immune response in humans. The immunogenicity of the toxin portion of the immunotoxin has recently been overcome by using the human analog of RNase (Rybak et al. Proc. Nat. Acad. Sci., USA, 89: 3165 (1992)). The murine antibody portion, however, is still significantly immunogenic (Sawler et al., J. Immunol., 135: 1530 (1985)).
Immunogenicity could be avoided and toxicity reduced if high affinity tumor specific human antibodies were available. However, the production of human monoclonal antibodies using conventional hybridoma technology has proven extremely difficult (James et al, J. Immunol Meth., 100: 5 (1987)). Furthermore, the paucity of purified tumor-specific antigens makes it necessary to immunize with intact tumor cells or partially purified antigen. Most of the antibodies produced react with antigens which are also common to normal cells and are therefore unsuitable for use as tumor-specific targeting molecules.